Samples and data are analyzed from a longitudinal population study conducted from 1965 to 2007 that allows study of the risk factors and effects of diabetes mellitus. Risk factors for obesity, hypertension, and nephropathy are also studied, along with the relationships of these diseases to diabetes and their effects on development of vascular complications and mortality. The genetics of diabetes is studied by means of family studies and relationships of genetic markers to disease. These findings are reported in DK069028 (Genetic epidemiology of diabetes and obesity) and DK069094 (Genetic epidemiology of diabetic complications). Findings related to kidney complications of diabetes are reported in DK069062 (Epidemiology, pathophysiology and treatment of diabetic nephropathy). Other findings published this fiscal year are summarized here. Comparison of 1- and 2-hour post-load plasma glucose in predicting diabetic eye disease. We compared the ability of 1- and 2-h plasma glucose concentrations (1h-PG and 2h-PG, respectively), derived from a 75-g oral glucose tolerance test (OGTT), to predict diabetic retinopathy. Cross-sectional (n = 2,895) and longitudinal (n = 1,703) cohorts were assessed for the prevalence and incidence of retinopathy, respectively, in relation to deciles of 1h-PG and 2h-PG concentrations. 1h-PG is a useful predictor of retinopathy risk, has a predictive value similar to that of 2h-PG, and may be considered as an alternative glucose time point during an OGTT.(14) A multicenter study of genetic susceptibility to type 2 diabetes. To identify common or rare genetic variation with potential therapeutic implications for T2D, we analyzed and replicated genome-wide protein coding variation in a total of 8,227 individuals with T2D and 12,966 individuals without T2D of Latino descent. We identified a novel genetic variant in the IGF2 gene associated with 20% reduced risk for T2D.(10) Autoantibodies predicting type 2 diabetes. The adaptive immune system is involved in type 2 diabetes mellitus (T2DM), indicating the presence of unidentified autoantibodies that might be useful biomarkers for emerging immunomodulatory therapy. Anti-PFDN2 antibodies were associated with T2DM. These findings indicate that autoimmunity may play a role in T2DM in Southwest American Indians.(2) Epigenetic mechanisms for high risk of type 2 diabetes in offspring of diabetic mothers. We performed an epigenome-wide association study to examine whether differential DNA methylation, a major source of epigenetic regulation, can be observed in offspring of mothers with type 2 diabetes during the pregnancy compared with offspring of mothers with no diabetes during the pregnancy. Intrauterine exposure to diabetes affected methylation at multiple genomic sites. Methylation status at some of these sites can impair insulin secretion, increase body weight and increase risk of type 2 diabetes.(3) Extension of studies of arsenic in diabetes susceptibility. In previous progress reports, we summarized our studies of associations of arsenic and other environmental pollutants with risk of type 2 diabetes in adult American Indians. Little is known about arsenic and diabetes in youth. We examined the association of arsenic with type 1 and type 2 diabetes in the SEARCH for Diabetes in Youth Case-Control study. Different arsenic metabolites were associated with type 1 diabetes in youth. These data support further research on the role of arsenic metabolism in type 1 diabetes, including the interplay with one-carbon metabolism biomarkers.(5) Genetic factors related to geographic differences in the prevalence of diabetes in Pima Indians in Mexico and the United States. Prevalence of diabetes and obesity in Mexican Pima Indians is low, while prevalence in US Pima Indians is high. Although lifestyle likely accounts for much of the difference, the role of genetic factors is not well explored. The largest differences between the subjects in Mexico and the US were at HLA markers. These results suggest that, in addition to the widely recognized balancing selection at HLA, recent directional selection may also occur, resulting in marked allelic differentiation between closely related populations.(7) Genetic studies of serum triglyceride concentrations in American Indians. Identity-by-descent mapping using empirical estimates of identity-by-descent allele sharing were used to identify genetic factors influencing serum triglyceride concentrations. APOC3/APOA5 constitutes a major locus for serum triglycerides in Amerindians, especially the Pimas, and these results provide an empirical example for the concept that population-based linkage analysis is a useful strategy to identify complex trait variants.(8) Association of genetic factors identified in Asians with diabetes in American Indians. Eight new loci for type 2 diabetes mellitus (T2DM) were identified in an East Asian genomewide association study metaanalysis. We assess tag SNPs across these loci for associations with T2DM in American Indians. Replication of lead T2DM SNPs in GLIS3, KCNK16, and ZFAND3 was observed in American Indians. Sexspecific T2DM signals in GLIS3 and ZFAND3, which are distinct from the East Asian GWAS signals, were also identified.(11) Insulin-like growth factor 1 receptor genetic variant associated with type 2 diabetes. We analyzed the IGF1R locus was analyzed as a candidate gene for type 2 diabetes (T2D) in American Indians. A unique G310D variant in IGF1R, which occurs in 6% American Indians, may impair IGF1R signaling pathways, thereby increasing the risk of T2D.(12) Severe obesity and risk of early onset type 2 diabetes. We studied metabolic alterations and type 2 diabetes risk among American Indian children who are obese or severely obese. We found that severe obesity in an American Indian population is a major driver of type 2 diabetes developing in adolescents and young adults.(18) Serum lipids and mortality in American Indians. In Caucasians, lower triglycerides (TG), total or LDL cholesterol and high HDL cholesterol are generally associated with lower mortality. However, low cholesterol is associated with higher mortality in some Asian populations. This study examines the relationship between serum lipids and mortality in American Indians. Cardiovascular mortality was positively associated with total, LDL and non-HDL cholesterol whereas lower lipid concentrations were adversely associated with mortality from liver disease or external causes, except for HDL cholesterol, where associations were positive. The common belief that low cholesterol and TG are beneficial for health is not universally observed; evidence suggests increased mortality at both ends of the cholesterol and TG distributions.(19) Preventing diabetes. Knowledge of diabetes risk factors coming from this and other studies led to the hypothesis that type 2 diabetes could be prevented or delayed in adults at high short-term risk. This hypothesis was confirmed in the Diabetes Prevention Program (DPP), a multicenter randomized clinical trial in which many of the participants and investigators in this project participated. We are now in a long-term follow-up phase, the Diabetes Prevention Program Outcomes Study (DPPOS), to assess long-term success with weight loss, reduction in the incidence of diabetes, and effects on diabetes complications. This study is reported in DK075078 (Prevention of type 2 diabetes).